The overall and specific goal of this application is the identification of novel high affinity and selective functional agonists of the nociceptin receptor that can be used to treat cocaine addiction. In previous efforts, we have identified, designed and synthesized novel, potent, and selective nociceptin receptor (a.k.a. ORL-1, NOP) agonists as tools for research on substance dependence with potential as clinically effective therapeutic agents. The disease target, cocaine abuse, represents an enormous health burden on society and for which currently available pharmacotherapies have insufficient efficacy. We propose nociceptin receptor agonism as a mechanism to achieve the therapeutic objective. Studies suggest that nociceptin activation opposes the dependence effects of substances of abuse such as nicotine, alcohol and cocaine. We propose nociceptin receptor activation as a mechanism to achieve the therapeutic objective of reduced cocaine addiction. While no clinical validation exists for the mechanism, the hypothesis supported by preclinical data, and would benefit from directed studies using optimized ligands, such as those we propose, to uncover the contributions of the nociceptin receptor to cocaine abuse as the first steps in developing novel therapeutics. In this application, we extend this molecule development program to center on the design, synthesis and evaluation of agents for that can be used in cocaine addiction research with potential to become therapeutics based on their actions at the nociceptin receptor. The pharmacology of novel compounds will be assessed in multiple cell-based assays and will include opioid receptor counterscreens to routinely determine potency and selectivity at a very early stage. The compound starting points for this project show no addictive potential, and a high level of selectivity over the mu opioid receptor, an improvement over currentiy available NOP agonists. This application is aimed at the development of the idea that nociceptin receptor agonists can be used to treat cocaine abuse. RELEVANCE (See instructions): Cocaine use represents an enormous worldwide health burden, in the US alone in 2009 more than 4.8 million people abused cocaine. Current cocaine use therapies are simply not effective and novel therapeutics are greatly needed. This project will test the hypothesis that the nociceptin receptor is involved in cocaine reward pathways in an attempt to validate the nociceptin receptor as a target for novel therapeutics to treat cocaine abuse.